The research, by the Genetic Investigation of ANthropometric Traits (GIANT) consortium, identifies genetic variants associated with obesity that are central to developing targeted interventions that can reduce the risks of chronic illnesses to which obesity contributes in significant ways.
Genome-wide association studies previously identified 49 loci (positions along a chromosome where the related genetic variants are located) that predispose individuals to a higher waist-to-hip ratio (WHR), a way to assess body-fat distribution. Lower values of WHR are associated with lower incidence of these diseases.
In this study, that included more than 476,000 individuals from more than 70 different study sites, focused specifically on coding variations, which have the potential to change the function of genes and their proteins. The team found 24 variations that predispose to higher WHR. Further analysis revealed pathways that influenced not only metabolism, but also the regulation of body fat tissue, bone growth and adiponectin, a hormone that controls glucose levels and breaks down fat. The team also performed functional studies across other organisms and identified two genes that affect body fat accumulation across species.
Professor Anne Justice, an assistant professor at the Center for Biomedical and Translational Informatics, Geisinger, former postdoctoral researcher at the University of North Carolina (UNC) and joint lead author of the research said, "A better understanding of the genetic underpinnings of body fat distribution may lead to better treatments for this highly prevalent disease and the cascade of downstream diseases obesity also impacts."
Professor Kari E. North of the Department of Epidemiology at UNC's Gillings School of Global Public Health and joint lead author said, "The study is one of the largest ever to explore the influence of low frequency and rare coding variation in body-fat distribution. The information the team collected on the impacts of the rarer variants they discovered is particularly valuable."
"For the first time we were able to look at, on a large scale, how low-frequency and rare variants influence body fat distribution," said Professor Cecilia Lindgren of the Big Data Institute at the University of Oxford. "These variants are rarer in the population, but the effects they have on individuals are much larger, possibly making them more clinically relevant."
Ruth Loos, PhD, professor at The Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount, and Director of the Genetics of Obesity and Related Metabolic Traits Program at Mount Sinai said, "By knowing the genes that determine where excess fat will be stored - is it preferentially at the hips or more often at the waist - we are a step closer in understanding the biology that explains why some people, when they gain weight, are at risk of diabetes or cardiovascular disease, and why others are not. "
Another major finding from this study is the importance of lipid metabolism to bodyfat distribution, which could lead to a better understanding of the causal influence of body fat distribution on downstream diseases like type 2 diabetes and cardiovascular disease.
Examining these less common and potentially protein changing genetic variations is an important step forward in understanding how genetics, body fat distribution, and chronic illnesses are linked together. However, that more work needs to be done to further explore how the changes manifest and how they can be harnessed to improve health outcomes.
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Notes to Editors:
About the Genetic Investigation of ANthropometric Traits (GIANT) consortium
The Genetic Investigation of ANthropometric Traits (GIANT) consortium is an international collaboration that seeks to identify genetic loci that modulate human body size and shape, including height and measures of obesity. The GIANT consortium is a collaboration between investigators from many different groups, institutions, countries, and studies, and the results represent their combined efforts. https://portals.broadinstitute.org/collaboration/giant/index.php/Main_Page
About the Big Data Institute
The Big Data Institute is located in the Li Ka Shing Centre for Health Informatics and Discovery at the University of Oxford. It is an interdisciplinary research centre that focuses on the analysis of large, complex data sets for research into the causes, consequences, prevention and treatment of disease. Research is conducted in areas such as genomics, population health, infectious disease surveillance and the development of new analytic methods. The Big Data Institute is supported by funding from the Medical Research Council, the UK Research Partnership Investment Fund, the National Institute for Health Research Oxford Biomedical Research Centre, and philanthropic donations from the Li Ka Shing and Robertson Foundations. Further details are available at http://www.bdi.ox.ac.uk
About the UNC Gillings School of Global Public Health
Established in 1940, the University of North Carolina at Chapel Hill Gillings School of Global Public Health is the #1 public school of public health in the U.S., tied for #2 among all schools, private and public, according to U.S. News & World Report rankings. Eight academic units (biostatistics, environmental sciences and engineering, epidemiology, health behavior, health policy and management, maternal and child health, nutrition and a public health leadership program) educate and train about 1,600 students each year, offering bachelor's, master's and doctoral degrees, as well as certificates and continuing education.
The Gillings School long has been a collaborative partner with the four other health affairs schools (dentistry, medicine, nursing and pharmacy) located in close proximity on the UNC-Chapel Hill campus, as well as with academic institutions and agencies across the U.S. and around the world. Our groundbreaking research, teaching and service are at work in all 100 N.C. counties and in more than 60 countries.
Accredited by the Council on Education for Public Health, the Gillings School employs about 240 faculty members and 311 full-time staff members. Grants and contracts awarded to School faculty members in FY 2018 amounted to $193.7 million, an average of $1.1 million per principal investigator. More than 99 percent of our students have jobs or plans to continue their education within one year after graduation.
The Gillings School's mission is to improve public health, promote individual well-being and eliminate health inequities across North Carolina and around the world. Read more about our mission and values at sph.unc.edu/mission.
About the University of North Carolina
The University of North Carolina at Chapel Hill, the nation's first public university, is a global higher education leader known for innovative teaching, research and public service. Every day, faculty, staff and students shape their teaching, research and public service to meet North Carolina's most pressing needs in every region and in all 100 counties. Carolina's nearly 330,000 alumni live in all 50 states, the District of Columbia, U.S. Territories and 161 countries.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.
For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.
Journal
Nature Genetics